CA2264513C - Substituted benzocycloheptapyridine derivatives useful for inhibition of farnesyl protein transferase - Google Patents

Abstract

Novel compounds of formula (1.0) are disclosed. Compounds of formula (1.0) are represented by the compounds of formulas (1.4) or (1.5) wherein R1, R3 and R4 are each independently selected from halo. W represents a group selected from (a), (b), (c) or (d). Also disclosed are methods of inhibiting farnesyl protein transferase and the growth of abnormal cells, such as tumor cells.

Description

W0 98/1 1099CA 02264513 1999-03-02PCT/US97/15905SUBSTITUTED BENZOCYCLOHEPTAPYRIDINE DERIVATIVES USEFUL FOR INHIBITION OFFARNESYL PROTEIN TRANSFERASE510152025EACKGBQUNDWO 95/10516, published April 20, 1995 discloses tricycliccompounds useful for inhibiting farnesyl protein transferase.In view of the current interest in inhibitors of farnesyl proteintransferase, a welcome contribution to the art would be compounds usefulfor the inhibition of farnesyl protein transferase. Such a contribution isprovided by this invention.SUMMARY OF THE INVENTIONThis invention provides compounds useful for the inhibition offarnesyl protein transferase (FPT). The compounds of this invention arerepresented by the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein:one of a, b, c and d represents N or NR9 wherein R9 is 0', -CH3 or-(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groupsrepresent CR1 or CR2; oreach of a, b, c, and d are independently selected from CR1 or CR2;each R1 and each R2 is independently selected from H, halo, -CF3,-OHIO (e.g., -OCH3), -COFIIO, -SFi1° (e.g., -SCH3 and -SCH2C5H5),-S(O)tFi11 (wherein t is 0, 1 or 2, e.g., —SOCH3 and 'SO2CI"'I3), -SCN,-N(Fi1°)2, -NFUOR“, -N02, —oc(o)R10, —CO2Fi1°, -OCO2Fl11, -CN,-NHC(O)Fi10, -NHSO2Fi‘0, -CONHR10, 'CONHCH2CH2OH,-NRWCOOFW,W0 98/1 10991015202530CA 02264513 1999-03-02PCT/US97/15905O)L N 3H O-SR11C(O)OFi“ (e.g., -SCHgCO2CH3), -SR“N(R75)g wherein each R75is independently selected from H and -C(O)OFI“ (e.g.,—S(CH2)2NHC(O)O-t-butyl and -S(CH2)2NH2), benzotriazol-1-yloxy,tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substitutedtetrazol-5-ylthio such as 1-methyl-tetrazol-5—y|thio), alkynyl, alkenyl oralkyl, said alkyl or alkenyl group optionally being substituted with halo,-OFl1° or -COgFl1°;R3 and R4 are the same or different and each independentlyrepresents H, any of the substituents of FI1 and R2, or R3 and R4 takentogether represent a saturated or unsaturated C5-C7 fused ring to thebenzene ring (Ring III);R5, R5, R7 and R3 each independently represents H, -CF3, —COR1°,alkyl or aryl, said alkyl or aryl optionally being substituted with —OR10,-SR10, -S(O)tR“, -NFIWCOOR11, -N(R1°)2, -N02, -COR10, -OCORW,'OCO2R11, -CO2R‘°, OPO3R1° or R5 is combined with R5 to represent =0or =S and/or R7 is combined with R3 to represent =0 or =8;R10 represents H, alkyl, aryl, or aralkyl (e.g., benzyl);R1‘ represents alkyl or aryl;X represents N, CH or C, which C may contain an optional doublebond (represented by the dotted line) to carbon atom 11;the dotted line between carbon atoms 5 and 6 represents anoptional double bond, such that when a double bond is present, A and Bindependently represent -R10, halo, -OR“, -OCOQFI“ or -OC(O)FI1°, andwhen no double bond is present between carbon atoms 5 and 6, A and Beach independently represent H2, -(OFl“)2; H and halo, dihalo, alkyl andH, (a|kyl)2, -H and -OC(O)R1°, H and -OR10, =0, aryl and H, =NOR1° or-O-(CH2)p-O- wherein p is 2, 3 or 4; andW represents a group selected from:H H H 12 HI I I ,R I / I—c—c—cH2oH —C—C—N\ ——C—C—N Y —c—c-o—R14l l I I R13 I II \ I IIH OH _ H 0 , H 0 0, H 0wherein:W0 98/1109910152025CA 02264513 1999-03-02PCT/U S97/ 15905- 3 _R12 is selected from the group consisting of: (1) H; (2) alkyl (e.g.,methyl and ethyl); (3) aryl; (4) arylalkyl (aralkyl);R13 is selected from the group consisting of: (1) H; (2) alkyl (e.g.,methyl and ethyl); (3) alkoxy (e.g., methoxy); (4) heterocycloalkyl, e.g., (a)tetrahydopyranyl, and (b) substituted tetrahydropyranyl wherein saidsubstituents are selected from hydroxy and hydroxyalkyl (e.g.,hydroxymethyl), for example D—galactosyl, i.e.,OHHO,“ OHOH -(5) aryl; and (6) aralkyl, e.g., benzyl;R14 is selected from the group consisting of: (1) H; (2) alkyl (e.g.,-C(CH3)3); (3) aryl; and (4) heteroaryl;ringN/{Yrepresents a heterocycloalkyl ring wherein Y represents the remainder ofthe ring, said remainder comprising carbon atoms and optionally a heteroatom selected from the group consisting of: NH, NR15, O and S, and saidremainder optionally having an aryl ring (e.g., phenyl) fused thereto;generally the heterocycloalkyl ring contains 4 or 5 carbon atoms andusually 4 carbon atoms, examples include:15/N ,examples of a heterocycloalkyl ring having a aryl ring fused to theremainder Y include\<":©R15 represents -C(O)OR15; andR15 represents alkyl, preferably -C(CH3)3.The compounds of this invention: (i) potently inhibit farnesyl proteintransferase, but not geranylgeranyl protein transferase I, in vitro; (ii) blockthe phenotypic change induced by a form of transforming Ras which is afarnesyl acceptor but not by a form of transforming Ras engineered to be aW0 98/1 1099101520253035CA 02264513 1999-03-02PCT/US97/15905. 4 -geranylgeranyl acceptor; (iii) block intracellular processing of Ras which isa farnesyl acceptor but not of Flas engineered to be a geranylgeranylacceptor; and (iv) block abnormal cell growth in culture induced bytransforming Ras.The compounds of this invention inhibit farnesyl protein transferaseand the famesylation of the oncogene protein Ras. Thus, this inventionfurther provides a method of inhibiting ras farnesyl protein transferase,(e.g., ras farnesyl protein transferase) in mammals, especially humans, bythe administration of an effective amount of the tricyclic compoundsdescribed above. The administration of the compounds of this invention topatients, to inhibit farnesyl protein transferase, is useful in the treatment ofthe cancers described below.This invention provides a method for inhibiting or treating theabnormal growth of cells, including transformed cells, by administering aneffective amount of a compound of this invention. Abnormal growth ofcells refers to cell growth independent of normal regulatory mechanisms(e.g., loss of contact inhibition). This includes the abnormal growth of: (1)tumor cells (tumors) expressing an activated Ras oncogene; (2) tumorcells in which the Ras protein is activated as a result of oncogenicmutation in another gene; and (3) benign and malignant cells of otherproliferative diseases in which aberrant Ras activation occurs.This invention also provides a method for inhibiting or treatingtumor growth by administering an effective amount of the tricycliccompounds, described herein, to a mammal (e.g., a human) in need ofsuch treatment. In particular, this invention provides a method forinhibiting or treating the growth of tumors expressing an activated Rasoncogene by the administration of an effective amount of the abovedescribed compounds. Examples of tumors which may be inhibited ortreated include, but are not limited to, lung cancer (e.g., lungadenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma suchas, for example, exocrine pancreatic carcinoma), colon cancers (e.g.,colorectal carcinomas, such as, for example, colon adenocarcinoma andcolon adenoma), myeloid leukemias (for example, acute myelogenousleukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome(MDS), bladder carcinoma, epidermal carcinoma, breast cancer andprostate cancer.It is believed that this invention also provides a method for inhibitingor treating proliferative diseases, both benign and malignant, wherein RasW0 98/1 10991015202530CA 02264513 1999-03-02PCT/U S97/ 15905- 5 -proteins are aberrantly activated as a result of oncogenic mutation in othergenes--i.e., the Ras gene itself is not activated by mutation to anoncogenic form--with said inhibition or treatment being accomplished bythe administration of an effective amount of the tricyclic compoundsdescribed herein, to a mammal (e.g., a human) in need of such treatment.For example. the benign proliferative disorder neurofibromatosis, ortumors in which Ras is activated due to mutation or overexpression oftyrosine kinase oncogenes (e.g., neu, src, abl, Ick, and fyn), may beinhibited or treated by the tricyclic compounds described herein.The tricyclic compounds useful in the methods of this inventioninhibit or treat the abnormal growth of cells. Without wishing to be boundby theory, it is believed that these compounds may function through theinhibition of G-protein function, such as ras p21, by blocking G-proteinisoprenylation, thus making them useful in the treatment of proliferativediseases such as tumor growth and cancer. Without wishing to be boundby theory, it is believed that these compounds inhibit ras farnesyl proteintransferase, and thus show antiproliferative activity against rastransformed cells.DETAILED DESCRIPTION OF THE INVENTI NAs used herein, the following terms are used as defined below unless otherwise indicated:MH+-represents the molecular ion plus hydrogen of the moleculein the mass spectrum;benzotriazol-1-yloxy represents1-methyl-tetrazol-5-ylthio representsN —NI] \N\II\I)\S\CH3 .alkenyl-represents straight and branched carbon chains having atleast one carbon to carbon double bond and containing from 2 to 12carbon atoms, preferably from 2 to 6 carbon atoms and most preferablyfrom 3 to 6 carbon atoms;W0 98/1 10991015202530CA 02264513 1999-03-02PCT/US97/15905_ 5 -alkynyl-represents straight and branched carbon chains having atleast one carbon to carbon triple bond and containing from 2 to 12 carbonatoms, preferably from 2 to 6 carbon atoms;alkyl-(including the alkyl portions of alkoxy, aralkyl andheteroarylalkyl)-represents straight and branched carbon chains andcontains from one to twenty carbon atoms, preferably one to six carbonatoms;aralkyl-represents an aryl group, as defined below, bound to analkyl group, as defined above, preferably the alkyl group is -CH2-, (e.g.,benzyl);aryl (including the aryl portion of aralkyl)-represents a carbocyclicgroup containing from 6 to 15 carbon atoms and having at least onearomatic ring (e.g., aryl is a phenyl ring), with all available substitutablecarbon atoms of the carbocyclic group being intended as possible pointsof attachment, said carbocyclic group being optionally substituted (e.g., 1to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3,amino, alkylamino, dialkylamino, -COOFi1° or -N02;—CHg-imidazolyl represents an imidazolyl group bound by anysubstitutable carbon of the imidazole ring to a -CH2-, that is:5: S-<.=*E />I-I N ,such as -CH2-(2-, 4- or 5-)imidazolyl, for example—I'{—(/ii“i, N’halo-represents fluoro, chloro, bromo and iodo;heteroaryl-represents cyclic groups, optionally substituted with R3and R4, having at least one heteroatom selected from O, S or N, saidheteroatom interrupting a carbocyclic ring structure and having a sufficientnumber of delocalized pi electrons to provide aromatic character, with thearomatic heterocyclic groups preferably containing from 2 to 14 carbonatoms, e.g., (2-, 4- or 5-)imidazolyl, triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide canbe represented as:W0 98/ l 109910152025CA 02264513 1999-03-02PCT/US97/15905- 7 -E , L, °' L ,N N NI l_ lO OOIheteroarylalkyl (heteroaralky|)-represents a heteroaryl group, asdefined above, bound to an alkyl group, as defined above, preferably thealkyl group is -CH2- (e.g., -CH2-(4- or 5-)imidazoly|);heterocycloalkyl-represents a saturated, branched or unbranchedcarbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 heterogroups selected from -O-, -S- or - NR10-; suitable heterocycloalkyl groupsinclude: (1) 2- or 3-tetrahydrofuranyl, (2) 2- or 3- tetrahydrothienyl, (3) 2-,3- or 4-piperidinyl, (4) 2- or 3-pyrrolidinyl, (5) 2- or 3-piperazinyl, (6) 2- or4-dioxanyl, (7) tetrahydopyranyl, and (8) substituted tetrahydropyranylwherein said substituents are selected from hydroxy and hydroxyalkyl(e.g., hydroxymethyl), for example, l?)-galactosyl, e.g.,HO“ onOHThe following solvents and reagents are referred to herein by theabbreviations indicated: ethanol (EtOH); methanol (MeOH); acetic acid(HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF);trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzo-triazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC); diisobutyl aluminum hydride (DIBAL);and 4-methylmorpholine (NMM).Reference to the position of the substituents R1, R2, R3, and R4 isbased on the numbered ring structure:4 5 6 73c”d -l I \ °5- 9Those skilled in the art will also appreciate that the S and Rstereochemistry at the C-11 bond are:CA 02264513 1999-03-02W0 98/ 11099 PCT/US97/l5905/ l 100x/'\I\J'\/\.f‘ J\J\f\/\l"Compounds of Formula 1.0 include compounds wherein thebottom piperidinyl group is a 4- or 3-piperidinyl group, i.e.,A B A\\ I OI‘ 5 Compounds of Formula 1.0 include compounds wherein R2 and R4are H, and R1 and R3 are halo (preferably independently selected from Bror Cl). For example, R1 is Br and R3 is Cl. These compounds includecompounds wherein R1 is in the 3-position and R3 is in the 8-position, e.g.,3-Br and 8-Cl. Compounds of Formula 1.0 also include compounds10 wherein R2 is H, and R‘, R3 and R4 are halo (preferably independentlyselected from Br or Cl).Preferably, compounds of Formula 1.0 are represented bycompounds of Formula 1.1: 15 wherein all substituents are as defined for Formula 1ØPreferably, R2 is H and R‘, R3 and R4 are halo; a is N and b, c andd are carbon; A and B are each H2; the optional bond between C5 and C6is absent; X is CH; and R5, R5, R7 and R3 are H. More preferably, R‘, R3CA 02264513 1999-03-02W0 98/ 11099 PCT/US97/15905-9-and R4 are independently selected from Br or Cl. Most preferably, R1 isBr, and R3 and R4 are independently selected from CI and Br.More preferably, compounds of Formula 1.0 are represented bycompounds of Formula 1.2 and Formula 1.3:wherein R‘, R3 and R4 are each independently selected from halo,preferably, Br or Cl; and A, B, X and W are as defined for Formula 1Ø10 More preferably, A and B are each H2; the optional bond between C5 andC6 is absent; and X is CH. Most preferably, R1 is Br; R3 and R4 areindependently Br or Cl, and still more preferably R3 is Cl and R4 is Br; A-and B are each H2; the optional bond between C5 and C6 is absent; X isCH; and R5, R5, R7 and R5 are H.15 When W represents:II‘! ’R12—C—C—N\:, ll preferably R12 is selected from the group consisting of: H, alkyl (mostpreferably methyl or ethyl) and aralkyl (most preferably benzyl); andpreferably R13 is selected from the group consisting of: H, alkyl (most20 preferably methyl or ethyl), alkoxy (most preferably methoxy), aralkyl (mostpreferably benzyl), and heterocycloalkyl (most preferably D—ga|actosyl).CA 02264513 1999-03-02W0 93/1 1099 PCT/U S97/ 15905_ 1o -Preferably: (1) R12 and R13 are H; (2) R12 is alkyl (e.g., methyl), and R13 isalkoxy (e.g., methoxy); (3) R12 is alkyl and R13 is alkyl (e.g, both R12 andR13 are ethyl); (4) Fl‘? is heterocycloalkyl (e.g., D-galactosyl) and R13 is H;or (5) R12 is aralkyl (e.g., benzyl) and R13 is H.5 When W representsii />-—C|:—C—N Yll \ON/\Ypreferably is selected from the group consisting of:0JL ,C(CH3)3 \0K\Nl-I (\N o < 10 /NJ , /NJ /N\/I and _93.‘.the heterocycloalkyl ringWhen W represents‘F— (l:— lc|—o— R14H 0R14 is preferably alkyl and most preferably -C(CH3)3.Compounds of Formulas 1.2A and 1.3A: 15are preferred when X is CH or N, and R‘, R3 and R4 are halo.The preferred compounds of this invention are represented by thecompounds of Formulas:CA 02264513 1999-03-02W0 98/11099 PCT/US97/15905-11- wherein R‘, R3 and R4 are halo and the remaining substituents are asdefined above, with the compounds of Formula 1.5A being morepreferred.5 Representative compounds of Formula 1.0 wherein W isH 12I ,R_-(I:-|(|:_N‘ 13H 0 Rinclude:10CA 02264513 1999-03-02W0 98/ 11099PCT/US97/15905-12-and HRepresentative compounds of Formula 1.0 wherein W isI /—?"°.'”\Y>H 0include:10 CA 02264513 1999-03-02W0 98/ 11099 PCTIUS97/ 15905-13-and Representative compounds of Formula 1.0 wherein W isHI— <|:— '(|:- o- R14H O10 include:CA 02264513 1999-03-02W0 98/1 1099 PCT/US97/ 15905-14-The compounds of this invention also include the 1-N-oxides--i.e,for example, compounds of the the formula:Br / \ C1wt\ H0 Br (1.6)N.rvv|vv~wherein ~’VVVV‘ represents the remainder of the compound, or10 pharmaceutically acceptable salts or solvates thereof.Optical rotation of the compounds ((+)- or (-)-) are measured inmethanol or ethanol at 25°C.W0 98/11099101520253035CA 02264513 1999-03-02PCTIUS97/15905- 15 _This invention includes the above compounds in the amorphousstate or in the cyrstalline state.Lines drawn into the ring systems indicate that the indicated bondmay be attached to any of the substitutable ring carbon atoms.Certain compounds of the present invention may exist in differentisomeric forms (e.g., enantiomers or diastereoisomers) includingatropisomers (i.e., compounds wherein the 7-membered ring is in a fixedconformation such that the 11-carbon atom is positioned above or belowthe plane of the fused beznene rings due to the presence of a 10—bromosubstituent). The invention contemplates all such isomers both in pureform and in admixture, including racemic mixtures. Enol forms are alsoincluded.Certain tricyclic compounds will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples ofsuch salts may include sodium, potassium, calcium, aluminum, gold andsilver salts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.Certain basic tricyclic compounds also form pharmaceuticallyacceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds havingbasic substituents such as amino groups also form salts with weakeracids. Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric,succinic, ascorbic, maleic, methanesulfonic and other mineral andcarboxylic acids well known to those in the art. The salts are prepared -bycontacting the free base form with a sufficient amount of the desired acidto produce a salt in the conventional manner. The free base forms may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammoniaand sodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubility inpolar solvents, but the acid and base salts are othen/vise equivalent totheir respective free base forms for purposes of the invention.All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and baseCA 02264513 2002-06-19-15..salts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.Compounds of the invention may be prepared according to the proceduresdescribed in WO 95/10516 published April 20, 1995, U.S. Patent 5,719,418, WO97/23478 published July 3, 1997 which discloses the subject matter of EP 1019392,EP 931079 and EP 0988300 and according to the procedures described below.Compounds of the invention can be prepared by reacting acompound of the formula:(12.0) wherein all substituents are as defined for Formula 1.0, with the appropriate protectedpiperidinyl acetic acid (e.g., 1-N-t—butoxycarbonylpiperidinyl acetic acid together withDEC/HOBT/NMM in DMF at about 25°C for about 18 hours to produce a compound of theformula: The compound of Formula 13.0 is then reacted either with TFA or 10% sulfuric acid indioxane and methanol followed by NaOH to produce the compound of Formula 14.0 CA 02264513 1999-03-02W0 98/1 1099 PCT/US97/15905can be prepared by reaction of a compound of Formula 12.0 with 1-N-t-5 butoxy-carbonylpiperidinyl-4-acetic acid as described above.For Example, compounds of Formula 15.0 include the compounds:BrCA 02264513 1999-03-02W0 98/1 1099 PCT/US97/ 15905 BrBr \ C1 Br \ C1\ / \ /N NBr \ C1 \ Cl\ , O \ ,Br \ C1The preparation of these compounds are described in PreparativeExamples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13, respectively, below.10 The compounds of the invention can be prepared by reacting acompound of the formula:CA 02264513 1999-03-02W0 98/1 1099 PCT/US97/15905-19-Br / \ ClBr(12.1)NlHwith the appropriate protected piperidinyl acetic acid (e.g., 1-N-t-butoxycarbonylpiperidinyl acetic acid together with DEC/HOBT/NMM inDMF at about 25°C for about 18 hours to produce a compound of the5 formula:Br / \ C1\ (13.1)N HasIBr 0N N 0L9 CH30 .The compound of Formula 13.1 is then reacted either with TFA or 10%sulfuric acid in dioxane and methanol followed by NaOH to produce thecompound of Formula 15.1Br /\ C1SN H (15.1)Br,HLG0 .The amide compounds of this invention, represented by Formula101.7CA 02264513 1999-03-02W0 98/ 1 1099 PCT/US97/15905-20-Br / \ c1\N (1 .7)can be prepared by reacting the compound of Formula 15.1 with theappropriate carboxylic acid in the presence of a coupling agent such asDEC and HOBT in dimethylformamide. Alternatively, the compound of5 Formula 15.1 can be reacted with an acid chloride or anhydride in asolvent such as pyridine.Compounds having an 1-N-O group: can be prepared from the corresponding pyridyl compounds:Br / \ C1KNBr (1.8)N1 0 ‘A/\l\/V‘by oxidation with meta-chloroperoxybenzoic acid. This reaction isconducted in a suitable organic solvent, e.g., dichloromethane (usuallyanhydrous) or methylene chloride, at a suitable temperature, to producethe compounds of the invention having the N-O substituent at position 1 of15 Ring I of the tricyclic ring system.Generally, the organic solvent solution of the starting tricyclicreactant is cooled to about 0°C before the m-chloroper-oxybenzoic acid isadded. The reaction is then allowed to warm to room temperature duringthe reaction period. The desired product can be recovered by standardCA 02264513 1999-03-02WO 98111099 PCT/US97/15905- ..separation means. For example, the reaction mixture can be washed withan aqueous solution of a suitable base, e.g., saturated sodiumbicarbonate or NaOH (e.g., 1N NaOH), and then dried over anhydrousmagnesium sulfate. The solution containing the product can be5 concentrated in vacuo. The product can be purified by standard means,e.g., by chromatography using silica gel (e.g., flash columnchromatography).Alternatively, N-O compounds can be made from intermediate: Br (12.1A)10 by the above oxidation procedure with m-chloroperoxybenzoic acid andBr /\ c1\N HBr (12.lB)NIQwherein Q is a protecting group, e.eg., BOC. After oxidation the protectinggroup is removed by techniques well known in the art. The N-Ointermediate are then reacted further to produce the compounds of the15 invention.Compounds of Formula 12.0 include the compound of Formula12.1:Br /\ C1\NBr (12.1)NIHThe compound of Formula 12.1 is prepared by methods known in the art,20 for example by methods disclosed in WO 95/10516, in U.S. 5,151,423 andCA 02264513 1999-03-02W0 98/ 11099 PCT/US97/15905- 22 _those described below. The above intermediate compound can also beprepared by a procedure comprising the following steps:(a) reacting an amide of the formulaR118 / |\N ONFl5aFl5a5 wherein R113 is Br, R53 is hydrogen and R53 is C1-C5 alkyl, aryl orheteroaryl; R53 is C1-C5 alkyl, aryl or heteroaryl and R53 is hydrogen; R53and R53 are independently selected from the group consisting of C1-C5alkyl and aryl; or R53 and R53, together with the nitrogen to which they areattached, form a ring comprising 4 to 6 carbon atoms or comprising 3 to 510 carbon atoms and one hetero moiety selected from the group consisting of-0- and -NR93-, wherein R931 is H, C1-C5 alkyl or phenyl;with a compound of the formulaR1aR7a R28RaaR4awherein R13, R23, R33 and R43 are are independently selected from the15 group consisting of hydrogen and halo and R73 is Cl or Br, in the presenceof a strong base to obtain a compound of the formulaR13Br / R28‘\o R33NR5“R5a Ft“(b) reacting a compound of step (a) with(i) POCI3 to obtain a cyano compound of the formulaR13Br / I R23‘N II R“N R“20 ; or(ii) DIBALH to obtain an aldehyde of the formulaCA 02264513 1999-03-02W0 98/11099 PCT/US97/15905- 23 -R18Br / R23\ IN 0 R33H R“(c) reacting the cyano compound or the aldehyde with a piperidinederivative of the formulaMgLNI5 wherein L is a leaving group selected from the group consisting of Cl andBr, to obtain a ketone or an alcohol of the formula below, respectively:Rte RtaR221or \N CH R33 (d)(i) cyclizing the ketone with CF3SO3H to obtain a compound ofFormula 13.0a wherein the dotted line represents a double bond; or10 (d)(ii) cyclizing the alcohol with polyphosphoric acid to obtain anIntermediate compound wherein the dotted line represents a single bond.Methods for preparing the Intermediate compounds disclosed inWO 95/10516, U.S. 5,151,423 and described below employ a tricyclicketone intermediate. Such intermediates of the formulaRlaR11b / R23\‘N15 °wherein FWD, R13, R23, R33 and R43 are independently selected from thegroup consisting of hydrogen and halo, can be prepared by the followingprocess comprising :(a) reacting a compound of the formulaRllbU20 N BrR3aWO 98/1 1099101520CA 02264513 1999-03-02PCTIUS97/15905- -(i) with an amine of the formula NHR5aR5a, wherein R56 andR53 are as defined in the process above; in the presence of a palladiumcatalyst and carbon monoxide to obtain an amide of the formula:Rm:‘V2?//:\2ONR5aR53; or(ii) with an alcohol of the formula R‘0aOH, wherein R103 isC1-C5 lower alkyl or C3-C5 cycloalkyl, in the presence of a palladiumcatalyst and carbon monoxide to obtain the ester of the formulaR11b/.\|N OOR10afollowed by reacting the ester with an amine of formula NHR5aR5a toobtain the amide;(b) reacting the amide with an iodo-substituted benzyl compound ofthe formulaR43 .wherein R13, R23, R33, R43 and R73 are as defined above, in the presenceof a strong base to obtain a compound of the formulaR13R11b R233a0 I RNR5an6a R“2;’ \§; and(c) cyclizing a compound of step (b) with a reagent of the formulaR3aMgL, wherein R33 is C1-C3 alkyl, aryl or heteroaryl and L is Br or Cl,provided that prior to cyclization, compounds wherein R53 or R53 ishydrogen are reacted with a suitable N-protecting group.(+)-isomers of compounds of Formula 12.2-CA 02264513 1999-03-02W0 98/11099 PCT/US97/15905- 25 -Br / \ C]SNBr (12.2)NIHcan be prepared with high enantioselectivity by using a processcomprising enzyme catalyzed transesterification. Preferably, a racemiccompound of Formula 12.3Br / \ C1\NI Br (12.3)1“5 His reacted with an enzyme such as Toyobo LIP-300 and an acylatingagent such as trifluoroethly isobutyrate; the resultant (+)-amide is thenisolated form the (-)-enantomeric amine by techniques well known in theart, and then the (+)-amide is hydrolyzed, for example by refluxing with an10 acid such as H2804, and the resulting compound is then reduced withDIBAL by techniques well known in the art to obtain the correspondingoptically enriched (+)-isomer of Formula 12.2. Alternatively, a racemiccompound of Formula 12.3, is first reduced to the corresponding racemiccompound of Formula 12.2 and then treated with the enzyme (Toyobo LIP-15 300) and acylating agent as described above to obtain the (+)-amide,which is hydrolyzed to obtain the optically enriched (+)-isomer.Those skilled in the art will appreciate that the compounds offormula 1.0 having other Fl‘, R3, R3, and R4 substituents may be made bythe above enzyme process.20 To produce the compounds of Formula 1.0, wherein W ISH 12 HI ,R I / l—c-c—N -—C—C—N Y —c- c—o—R”I ll ‘R13 || \ lH 0 H 0 or H 0the compounds of Formulas 14.0 or 15.0 are reacted with the appropriatehaloacetamide or haloacetate:CA 02264513 1999-03-02wo 9s/11099 PCT/US97/15905-25-H H HI ,1?” I / IX-C-C-N x—c—c—N Y x—c—c—o—R14I ll ‘R13 I II \ I llH o , H 0or H 0 ,respectively, wherein X is halo (e.g., Br or Cl) to alkylate the aminenitrogen of the piperidine ring. This reaction is conducted according toprocedures well known in the art. For example, the compounds of 5 Formulas 14.0 or 15.0 are reacted with the appropriate haloacetamide in asuitable organic solvent (e.g., DMF) with a suitable base (e.g., Na2CO3).For example, reaction of the compound of the formulawith the haloacetamides or haloacetatesH '12 H Hl ,R I / IX-C—C-N x—c-c—N Y) X-c-c-0-R14I ll ‘R13 I ll \ I ll10 H 0 , H 0 or H 0wherein X is Br or Cl, in DMF with NagCO3 yields compounds of theformulas WO 98/1 10991015CA 02264513 1999-03-02PCTIU S97/ 15905-27-respectively.Compounds of the invention are exemplified by the followingexamples, which should not be construed to limit the scope of thedisclosure.PREPARATIVE EXAMPLE 1\ / CO2Hte A:~ ‘ ——~ CO2Et C029‘Combine 10 g (60.5 mmol) of ethyl 4-pyridylacetate and 120 mL ofdry CHQCIQ at -20°C, add 10.45 g (60.5 mmol) of MCPBA and stir at -20°Cfor 1 hour and then at 25°C for 67 hours. Add an additional 3.48 g (20.2mmoles) of MCPBA and stir at 25°C for 24 hours. Dilute with CH2C|2 andwash with saturated NaHCO3 (aqueous) and then water. Dry over MgSO4,concentrate in vacuo to a residue, and chromatograph (silica gel, 2%-W0 98/ l 10991015CA 02264513 1999-03-02PCT/US97/15905-23-5.5% (10% NH4OH in MGOH)/CH2C|2)tO give 8.12 g of the productcompound. Mass Spec.: MH+ = 182.15&l3_B:\ / CO2Et \ / 002*!Combine 3.5 g (19.3 mmol) of the product of Step A, 17.5 mL ofEtOH and 96.6 mL of 10% NaOH (aqueous) and heat the mixture at 67°Cfor 2 hours. Add 2 N HCI (aqueous) to adjust to pH = 2.37 andconcentrate in vacuo to a residue. Add 200 mL of dry EtOH, filter throughcelite® and wash the filter cake with dry EtOH (2X50 ml). Concentrate thecombined filtrates in vacuo to give 2.43 g of the title compound.PREPARATIVE EXAMPLE 2o co2H(CH3)3C—OThe title compound is prepared via the process disclosed in PCTinternational Publication No. W095/10516.PREPARATIVE EXAMPLE 3Br \ Cl\ /N HOCA 02264513 1999-03-02W0 98/1 1099 PCT/U S97! 15905-29..Combine 14.95 g (39 mmol) of 8—chloro-11-(1-ethoxy-carbonyl-4-piperidinyl)-11H-benzo[5,6]cyc|ohepta[1,2-b]pyridine and 150 mL of5 CH2Cl2, then add 13.07 g (42.9 mmol) of (nBu)4NNO3 and cool themixture to 0°C. Slowly add (dropwise) a solution of 6.09 mL (42.9 mmol)of TFAA in 20 mL of CH2C|2 over 1.5 hours. Keep the mixture at 0°Covernight, then wash successively with saturated NaHCO3 (aqueous),water and brine. Dry the organic solution over Na2SO4, concentrate in10 vacuo to a residue and chromatograph the residue (silica gel,EtOAc/hexane gradient) to give 4.32 g and 1.90 g of the two productcompounds 3A(i) and 3A(ii), respectively.Mass Spec. for compound 3A(i): MH+ = 428.2;Mass Spec. for compound 3A(ii): MH+ = 428.3.15 Step 5: CO2Et CO2EtCombine 22.0 g (51.4 mmol) of the product 3A(i) from Step A, 150mL of 85% EtOH (aqueous), 25.85 g (0.463 mole) of Fe powder and 2.42W0 98/1 1099101520CA 02264513 1999-03-02PCT/U S97/ 15905-30-2 g (21.8 mmol) of CaCl2, and heat at reflux overnight. Add 12.4 g (0.222mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2hours. Add another 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8mmol) of CaC|2 and heat at reflux for 2 hours more. Filter the hot mixturethrough celite®, wash the celite® with 50 mL of hot EtOH and concentratethe filtrate in vacuo to a residue. Add 100 ml‘. of anhydrous EtOH,concentrate to a residue and chromatograph the residue (silica gel,MeOH/CH2C|2 gradient) to give 16.47 g of the product compound.Step Q:Combine 16.47 g (41.4 mmol) of the product from Step B, and 150mL of 48% HBr (aqueous) and cool to -3°C. Slowly add (dropwise) 18 mLof bromine, then slowly add (dropwise) a solution of 8.55 g (0.124 mole) ofNaNO2 in 85 mL of water. Stir for 45 minutes at -3° to 0°C, then adjust topH = 10 by adding 50% NaOH (aqueous). Extract with EtOAc, wash theextracts with brine and dry the extracts over Na2SO4. Concentrate to aresidue and chromatograph (silica gel, EtOAc/hexane gradient) to give10.6 g and 3.28 g of the two product compounds 3C(i) and 3C(ii),respectively.Mass Spec. for compound 3C(i): MH+ = 461.2;Mass Spec. for compound 3C(ii): MH+ = 539.W0 98/1 1099101520CA 02264513 1999-03-02PCT/US97I 15905-31- lCO2EtHydrolyze the product 3C(i) of Step C by dissolving in concentratedHCl and heating to about 100°C for @ 16 hours. Cool the mixture, theneutralize with 1 M NaOH (aqueous). Extract with CHQCIZ, dry the extractsover MgSO4, filter and concentrate in vacuo to the title compound.Mass Spec.: MH+ = 466.9.Step E: Dissolve 1.160 g (2.98 mmol) of the title compound from Step D in20 mL of DMF, stir at room temperature, and add 0.3914 g (3.87 mmol) of4-methyl-morpholine, 0.7418 g (3.87 mmol) of DEC, 0.5229 g (3.87 mmol)of HOBT, and 0.8795 g (3.87 mmol) of 1-N-t-butoxycarbonyl—piperidinyl-4-acetic acid. Stir the mixture at room temperature for 2 days, thenconcentrate in vacuo to s residue and partition the residue betweenCHgClg and water. Wash the organic phase successively with saturatedNaHCO3 (aqueous), 10% NaHgPO4 (aqueous) and brine. Dry the organicphase over MgSO4, filter and concentrate in vacuo to a residue.Chromatograph the residue (silica gel, 2% MeOH/ CH2Cl2 + NH3) to give1.72 g of the product. m.p. = 94.0-94.5°C, Mass Spec.: MH+ = 616.3,elemental analysis: calculated - C, 60.54; H, 6.06; N, 6.83found - C, 59.93; H, 6.62; N, 7.45.CA 02264513 1999-03-02W0 98/1 1099 PCT/US97/15905-32- Combine 1.67 g (2.7 mmol) of the product of Step E and 20 mL ofCH2Ci2 and stir at 0°C. Add 20 mL of TFA, stir the mixture for 2 hours,5 then basify the mixture with 1 N NaOH (aqueous). Extract with CHQCIQ,dry the organic phase over MgSO4, filter and concentrate in vacuo to give1.16 g of the product. m.p. = 140.2-140.8°C, Mass Spec.: MH+ = 516.2.PREPARATIVE EXAMPLE 4BrAOCHQCH3 0AOOCI-I2CI-13Combine 25.86 g (55.9 mmol) of 4-(8-chloro-3-bromo—5,6-dihydro-11H-benzo[5,6]cycIohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-15 carboxylic acid ethyi ester and 250 mL of concentrated H2804 at -5°C,then add 4.8 g (56.4 mmol) of NaNO3 and stir for 2 hours. Pour themixture into 600 g of ice and basify with concentrated NH4OH (aqueous).W0 98/1 1099101520CA 02264513 1999-03-02PCT/U S97/ 15905-33-Filter the mixture, wash with 300 mL of water, then extract with 500 mL ofCH2Cl2. Wash the extract with 200 mL of water, dry over MgSO4, thenfilter and concentrate in vacuo to a residue. Chromatograph the residue(silica gel, 10% EtOAc/ CH2C|2) to give 24.4 g (86% yield) of the product.m.p. = 165-167°C, Mass Spec.: MH+ = 506 (CI),elemental analysis: calculated - C, 52.13; H, 4.17; N, 8.29found - C, 52.18; H, 4.51;, N, 8.16.Step B: Ao OCHZCH3 oAocH2cH3Combine 20 g (40.5 mmol) of the product of Step A and 200 mL ofconcentrated H2304 at‘20°C, then cool the mixture to 0°C. Add 7.12 g(24.89 mmol) of 1,3-dibromo-5,5-dimethyl-hydantoin to the mixture and stirfor 3 hours at 20°C. Cool to 0°C, add an additional 1.0 g (3.5 mmol) of thedibromohydantoin and stir at 20°C for 2 hours. Pour the mixture into 400 gof ice, basify with concentrated NH4OH (aqueous) at 0°C, and collect theresulting solid by filtration. Wash the solid with 300 mL of water, slurry in200 mL of acetone and filter to provide 19.79 g (85.6% yield) of theproduct. m.p. = 236-237°C, Mass Spec.: MH+ = 584 (CI),elemental analysis: calculated - C, 45.11; H, 3.44; N, 7.17found - C, 44.95; H, 3.57; N, 7.16.Step C: WO 98/1109910152025CA 02264513 1999-03-02PCT/US97/ 15905- -Combine 25 g (447 mmol) of Fe filings, 10 g (90 mmol) of CaCl2and a suspension of 20 g (34.19 mmol) of the product of Step B in 700 mLof 90:10 EtOH/water at 50°C. Heat the mixture at reflux overnight, filterthrough Celite® and wash the filter cake with 2 X 200 mL of hot EtOH.Combine the filtrate and washes, and concentrate in vacuo to a residue.Extract the residue with 600 mL of CH2C|2, wash with 300 mL of water anddry over MgSO4. Filter and concentrate in vacuo to a residue, thenchromatograph (silica gel, 30% EtOAc/CH2C|2) to give 11.4 g (60% yield)of the product. m.p. = 211-212°C,Mass Spec.: MH+ = 554 (CI),elemental analysis: calculated - C, 47.55; H, 3.99; N, 7.56found - C, 47.45; H, 4.31; N, 7.49.mpg 0% OCH2CH3 O¢l\Slowly add (in portions) 20 g (35.9 mmol) of the product of Step Cto a solution of 8 g (116 mmol) of NaNO2 in 120 mL of concentrated HCI(aqueous) at -10°C. Stir the resulting mixture at 0°C for 2 hours, thenslowly add (dropwise) 150 mL (1.44 mole) of 50% H3PO2 at 0°C over a 1hour period. Stir at 0°C for 3 hours, then pour into 600 g of ice and basifywith concentrated NH4OH (aqueous). Extract with 2 X 300 mL of CH2Cl2,dry the extracts over MQSO4, then filter and concentrate in vacuo to aresidue. Chromatograph the residue (silica gel, 25% EtOAc/ hexanes) togive 13.67 g (70% yield) of the product. m.p. = 163-165°C, Mass Spec.:MH+ = 539 (CI),elemental analysis:OCHQCI-I3calculated - C, 48.97; H, 4.05; N, 5.22found- C, 48.86; H, 3.91; N, 5.18.CA 02264513 1999-03-02W0 98/1 1099 PCTlUS97/ 15905-35- A0 OCH_.,_CI-I3Combine 6.8 g (12.59 mmol) of the product of Step D and 100 mLof concentrated HCI (aqueous) and stir at 85°C overnight. Cool the5 mixture, pour it into 300 g of ice and basify with concentrated NH4OH(aqueous). Extract with 2 x 300 mL of CH2Cl2, then dry the extracts overMQSO4. Filter, concentrate in vacuo to a residue, then chromatograph(silica gel, 10% MeOH/EtOAc + 2% NH4OH (aqueous)) to give 5.4 g (92%yield) of the title compound. m.p. = 172-174°C, Mass Spec.: MH+ = 46710 (FAB),elemental analysis: ' calculated - C, 48.69; H, 3.65; N, 5.97found - C, 48.83; H, 3.80; N. 5.97.Step F:Following essentially the same procedure as Step C of Preparative15 Example 5 below, the title compound from Step E above is reacted with 1-N-t-butoxycarbonylpiperidinyl—4-acetic acid to produce the compound Step G:Following essentially the same procedure as Step D of Preparative20 Example 5 below, the title compound from Step F above is deprotected toyield the title compound of Preparative Example 4.WO 98/110991015CA 02264513 1999-03-02PCT/US97/15905- 35 -PREPARATIVE EXAMPLE 5BrCl0\\ /N A0Hydrolyze 2.42 g of 4-(8-chloro-3-bromo-5,6-dihydro-1 1 H-benzo[5,6]cyclohepta[1,2—b]pyridin-1 1-ylidene)-1-piperidine—1-carboxylicacid ethyl ester via substantially the same procedure as described inPreparative Example 3, Step D, to give 1.39 g (69% yield) of the product.Step B:OEtC132 Combine 1 g (2.48 mmol) of the product of Step A and 25 mL of drytoluene, add 2.5 mL of 1 M DIBAL in toluene and heat the mixture at reflux.After 0.5 hours, add another 2.5 mL of 1 M DIBAL in toluene and heat atreflux for 1 hour. (The reaction is monitored by TLC using 50%MGOH/CHQCIQ +NH4OH (aqueous).) Cool the mixture to roomtemperature, add 50 mL of 1 N HCI (aqueous) and stir for 5 min. Add 100mL of 1 N NaOH (aqueous), then extract with EtOAc (3 X 150 mL). Dry theextracts over MgSO4, filter and concentrate in vacuo to give 1.1 g of thetitle compound.CA 02264513 1999-03-02W0 98/11099 PCT/US97/15905- 37 _fitep Q:Br \\ /NNH Combine 0.501 g (1.28 mmol) of the title compound of Step B and20 mL of dry DMF, then add 0.405 g (1.664 mmol) of 1-N-t-5 butoxycarbonylpiperidinyi-4—acetic acid, 0.319 g (1.664 mmol) of DEC,0.225 g (1.664 mmol) of HOBT, and 0.168 g (1.664 mmol) of 4-methyimorphoiine and stir the mixture at room temperature overnight.Concentrate the mixture in vacuo to a residue, then partition the residuebetween 150 mL of CH2C|2 and 150 mL of saturated NaHCO3 (aqueous).10 Extract the aqueous phase with another 150 mL of CHp_C|2. Dry theorganic phase over MgSO4, and concentrate in vacuo to a residue.Chromatograph the residue (silica gel, 500 mL hexane, 1 L of 1%MeOH/CH2CI2 + 0.1% NH4OH (aqueous), then 1 L of 2% MeOH/CH2C|2 +0.1% NH4OH (aqueous)) to give 0.575 g of the product. m.p. = 115°-15 125°C; Mass Spec.: MH+ = 616.Step D: Combine 0.555 g (0.9 mmol) of the product of Step C and 15 mL ofCH2C|2 and cool the mixture to 0°C. Add 15 mL of TFA and stir at 0°C for20 2 hours. Concentrate in vacuo at 40-45°C to a residue, then partition theresidue between 150 mL of CH2Ci2 and 100 mL of saturated NaHCO3(aqueous). Extract the aqueous layer with 100 mL of CH2Ci2, combinethe extracts and dry over MgSO4. Concentrate in vacuo to give 0.47 g ofthe product.25 m.p. = 140°-150°C; Mass Spec.: MH+ = 516.CA 02264513 1999-03-02W0 98/11099 PCT/US97l15905- 33 -PREPARATIVE EXAMPLE 6BrBr \ C1\ /N[N]0[racemic as well as (+)- and (—)-isomers]Step A:BrCl A ,o OCH2CI-I3Combine 16.6 g (0.03 mole) of the product of Preparative Example4, Step D, with a 3:1 solution of CH3CN and water (212.65 mL CH3CNand 70.8 mL of water) and stir the resulting slurry overnight at roomtemperature. Add 32.833 g (0.153 mole) of NalO4 and then 0.31 g (2.3010 mmol) of FiuO2 and stir at room temperature give 1.39 g (69% yield) of theproduct. (The addition of FiuO is accompanied by an exothermic reactionand the temperature climbs from 20° to 30°C.) Stir the mixture for 1.3 hrs.(temperature returned to 25°C after about 30 min.), then filter to removethe solids and wash the solids with CH2C|2. Concentrate the filtrate in15 vacuo to a residue and dissolve the residue in CH2Cl2. Filter to removeinsoluble solids and wash the solids with CH2Cl2. Wash the filtrate withwater, concentrate to a volume of about 200 mL and wash with bleach,then with water. Extract with 6 N HCI (aqueous). Cool the aqueousextract to 0°C and slowly add 50% NaOH (aqueous) to adjust to pH = 420 while keeping the temperature <30°C. Extract twice with CH2Cl2, dry overMgSO4 and concentrate in vacuo to a residue. Slurry the residue in 20mL of EtOH and cool to 0°C. Collect the resulting solids by filtration andW0 98/1 109910152025CA 02264513 1999-03-02PCT/US97/15905-39-dry the solids in vacuo to give 7.95 g of the product. ‘H NMR (CDCI3, 200MHz): 8.7 (s, 1H); 7.85 (m, 6H); 7.5 (d, 2H); 3.45 (m, 2H); 3.15(m,2H).Step 3:Br*'*—-* \ /NOHCombine 21.58 g (53.75 mmol) of the product of Step A and 500mL of an anhydrous 1:1 mixture of EtOH and toluene, add 1.43 g (37.8mmol) of NaBH4 and heat the mixture at reflux for 10 min. Cool themixture to 0°C, add 100 mL of water, then adjust to pH= 4-5 with 1 M HCl(aqueous) while keeping the temperature <10°C. Add 250 mL of EtOAcand separate the layers. Wash the organic layer with brine (3 X 50 mL)then dry over Na2SO4. Concentrate in vacuo to a residue (24.01 g) andchromatograph the residue (silica gel, 30 % hexane/CHgCl2) to give theproduct. impure fractions were purified by rechromatography. A total of18.57 g of the product was obtained. ‘H NMR (DMSO-d5, 400 MHz): 8.5(s, 1H); 7.9 (s, 1H); 7.5 (d of d, 2H); 6.2 (s, 1H); 6.1 (s, 1H); 3.5 (m, 1H);3.4 (m, 1H); 3.2 (m, 2H).Step Q:BrBr Br \\ C1/Br \ c1 N\ / ———->Nonc;Combine 18.57 g (46.02 mmol) of the product of Step B and 500mL of CHCI3, then add 6.70 mL (91.2 mmol) of SOCI2, and stir the mixtureat room temperature for 4 hrs. Add a solution of 35.6 g (0.413 mole) ofpiperazine in 800 mL of THF over a period of 5 min. and stir the mixture for1 hr. at room temperature. Heat the mixture at reflux overnight, then coolto room temperature and dilute the mixture with 1 L of CHQCIQ. Wash withwater (5 X 200 mL), and extract the aqueous wash with CHCI3 (3 X 100mL). Combine all of the organic solutions, wash with brine (3 X 200 mL)and dry over MgSO4. Concentrate in vacuo to a residue and  CA 02264513 2002-06-19-40..chromatograph (silica gel, gradient of 5%, 7.5%. 10% MeOH/CHZCI2 + NH40H) to give18.49 g of the title compound as a racemic mixture.BrBr \ Q ClBr \ /NBr C1 N\ /N iNH[N] BrStep D - Sepagation of Enantiomers:NH Br Cl\ /N 5E”)NHThe racemic title compound of Step C is separated by preparative chiralchromatography (Chiralpack® ADTM, 5 cm X 50 cm column, flow rate 100 mL/min., 20%iPrOH/hexane + 0.2% diethylamine), to give 9.14 g of the (+)-isomer and 9.30 g of the (-)-isomer.Physical chemical data for (+)-isomer: m.p. = 74.5“-77.5°C; Mass Spec. MH+= 471.9; [(1120: = +97.4° (8.48 mg/2mL MeOH).Physical chemical data for (-)-isomer: m.p. = 82.9°-84.5°C; Mass Spec. MH+= 471.8; [oz] 3,; = —97.4° (8.32 mg/2mL MeOH).Step E:BrBl‘ Br \ ""‘ ClBr \ C1 N’\ N N (CH3)3C\0---->~ (3(-)-isomer N 0E j /KOHCombine 3.21 g (6.80 mmol) of the (-)-isomer product of Step D and 150 mL ofanhydrous DMF. Add 2.15 g (8.8 mmol) of 1-N—t— W0 98/1 1099101520CA 02264513 1999-03-02PCT/U S97/ 15905- 41 -butoxycarbonylpiperidinyl-4-acetic acid, 1.69 g (8.8 mmol) of DEC, 1.19 g(8.8 mmol) of HOBT and 0.97 mL (8.8 mmol) of N—methylmorpho|ine andstir the mixture at room temperature overnight. Concentrate in vacuo toremove the DMF and add 50 mL of saturated NaHCO3 (aqueous). Extractwith CH2Cl2 (2 X 250 mL), wash the extracts with 50 mL of brine and dryover MgSO4. Concentrate in vacuo to a residue and chromatograph(silica gel, 2% MeOH/CH2Cl2 + 10% NH4OH) to give 4.75 g of the product.m.p. = 75.7°-78.5°C; Mass Spec.: MH+ = 697; [oL]g5 = —5.5° (6.6 mg/2 mLMeOH).gtep F:Br BrBr \ Cl Br \ c1\ / \ /N NN (CH3)3C\NJ —* E 1we 0 0Combine 4.70 g (6.74 mmol) of the product of Step E and 30 mL ofMeOH, then add 50 mL of 10% H2804/dioxane in 10 mL aliquots over a 1hr. period. Pour the mixture into 50 mL of water and add 15 mL of 50%NaOH (aqueous) to adjust to pH—- 10-11. Filter to remove the resultingsolids and extract the filtrate with CH2C|2 (2 X 250 mL). Concentrate theaqueous layer in vacuo to remove the MeOH and extract again with 250mL of CH2C|2. Dry the combined extracts over MgSO4 and concentrate invacuo to give the product. m.p. = 128.1°-131.5°C; Mass Spec.: MH+ =597; [(1135 = -6.02° (9.3 mg/2 mL MeOH).OPREPARATIVE EXAMPLE 7Br Cl\\ /NIOCA 02264513 1999-03-02W0 98/ 11099 PCT/US97l15905-42.. A Ao OCH2CH3 0 0CH2CHsCombine 15 g (38.5 mmol) of 4-(8-chIoro-3-bromo—5,6-dihydro-1 1H-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1—y|idene)-1-piperidine-1-5 carboxylic acid ethyl ester and 150 mL of concentrated H2804 at -5°C,then add 3.89 g (38.5 mmol) of KNO3 and stir for 4 hours. Pour themixture into 3 L of ice and basify with 50% NaOH (aqueous). Extract withCH2Cl2, dry over MgSO4, then filter and concentrate in vacuo to a residue.Recrystallize the residue from acetone to give 6.69 g of the product. ‘H10 NMR (CDCI3, 200 MHz): 8.5 (s, 1H); 7.75 (s, 1H); 7.6 (s, 1H); 7.35 (s,1H); 4.15 (q, 2H); 3.8 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.8 (m, 2H); 2.6-2.2(m, 4H); 1.25 (t, 3H).3_t€2l3—B3 A 0% OCI-I2CH3o OCH2CI-I315 Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of85% EtOH/water, then add 0.66 g (5.9 mmol) of CaC|2 and 6.56 g (117.9mmol) of Fe and heat the mixture at reflux overnight. Filter the hot reactionmixture through celite® and rinse the filter cake with hot EtOH.Concentrate the filtrate in vacuo to give 7.72 g of the product. Mass Spec.:20 MH+ = 478ØW0 98/1 1099101520CA 02264513 1999-03-02PCTlUS97/ 15905-43- Ao OCH2CI-I3Ao OCH2CI-I3Combine 7.70 g of the product of Step B and 35 mL of HOAc, thenadd 45 mL of a solution of Bl'2 in HOAc and stir the mixture at roomtemperature overnight. Add 300 mL of 1 N NaOH (aqueous) , then 75 mLof 50% NaOH (aqueous) and extract with EtOAc. Dry the extract overMgSO4 and concentrate in vacuo to a residue. Chromatograph theresidue (silica gel, 20%-30% EtOAc/hexane) to give 3.47 g of the product(along with another 1.28 g of partially purified product). Mass Spec.: MH+= 555.9.‘H NMR (CDCI3, 300 MHz): 8.5 (s, 1H); 7.5 (s, 1H); 7.15 (s, 1H); 4.5 (s,2H); 4.15 (m, 3H); 3.8 (br s, 2H); 3.4-3.1 (m, 4H); 9-2.75 (m, 1H); 2.7-2.5(m, 2H); 2.4-2.2 (m, 2H); 1.25 (m, SH).Step D: AOCHZCI-I3A0 OCI-I2CI-I3 0Combine 0.557 g (5.4 mmol) of t—butylnitrite and 3 mL of DMF, andheat the mixture at to 60°-70°C. Slowly add (dropwise) a mixture of 2.00 g(3.6 mmol) of the product of Step C and 4 mL of DMF, then cool themixture to room temperature. Add another 0.64 mL of t-butylnitrite at 40°Cand reheat the mixture to 60°-70°C for 0.5 hrs. Cool to room temperatureand pour the mixture into 150 mL of water. Extract with CH2Cl2, dry theextract over MgSO4 and concentrate in vacuo to a residue.Chromatograph the residue (silica gel, 10%-20°/o EtOAc/hexane) to give0.74 g of the product. Mass Spec.: MH+ = 541ØW0 98/1 1099101520CA 02264513 1999-03-02PCT/US97/ 15905- 44 -‘H NMR (CDCI3, 200 MHz): 8.52 (s, 1H); 7.5 (d, 2H); 7.2 (s, 1H); 4.15 (q,2H); 3.9-3.7 (m, 2H); 3.5-3.1 (m,4H); 3._O-2.5(m,2H); 2.4-2.2 (m,2H);2.1-1.9 (m, 2H); 1.26 (t, 3H).fitei Ao OCH2CH3Combine 0.70 g (1.4 mmol) of the product of Step D and 8 mL ofconcentrated HCI (aqueous) and heat the mixture at reflux overnight. Add30 mL of 1 N NaOH (aqueous), then 5 mL of 50% NaOH (aqueous) andextract with CH2Cl2. Dry the extract over MgSO4 and concentrate invacuo to give 0.59 g of the title compound. Mass Spec.: M+ = 468.7. m.p.= 123.9°-124.2°C.Step F: React 6.0 g (12.8 mmol) of the title compound from Step E and with3.78 g (16.6 mmol) of 1-N—t-butoxycarbonylpiperidinyl-4-acetic acid usingsubstantially the same procedures as described for Preparative Example5, Step C, to give 8.52 g of the product. Mass Spec.: MH+ = 694.0 (FAB).‘H NMR (CDCI3, 200 MHz): 8.5 (d, 1H); 7.5 (d, 2H); 7.2 (d, 1H); 4.15-3.9(m, SH); 3.8-3.6 (m, 1H); 3.5-3.15 (m, SH); 2.9 (d, 2H); 2.8-2.5 (m, 4H);2.4-1.8 (m, 6H); 1.8-1.6 (br d, 2H); 1.4 (s, 9H); 1.25-1.0 (m, 2H).CA 02264513 1999-03-02W0 98/1 1099 PCT/U S97/ 15905-45- Combine 8.50 g of the product of Step F and 60 mL of CH2C|2, thencool to 0°C and add 55 mL of TFA. Stir the mixture for 3 h at 0°C, then add5 500 mL of 1 N NaOH (aqueous) followed by 30 mL of 50% NaOH(aqueous). Extract with CH2C|2, dry over MgSO4 and concentrate invacuo to give 7.86 g of the product. Mass Spec.: M+ = 593.9 (FAB). 1HNMR (CDCI3, 200 MHz): 8.51 (d, 1H); 7.52 (d of d, 2H); 7.20 (d, 1H); 4.1-3.95 (rn, 2H); 3.8-3.65 (m,. 2H); 3.5-3.05 (rn, 5H); 3.0-2.5 (rn, 6H); 2.45-10 1.6 (m, 6H);1.4-1.1 (m, 2H).PREPARATIVE EXAMPLE 8Br \ Cl\ /NBr0[racemic as well as (+)- and (-)-isomers] Prepare a solution of 8.1 g of the title compound from PreparativeExample 7, Step E, in toluene and add 17.3 mL of a 1M solution of DIBALCA 02264513 2002-06-19-46-in toluene. Heat the mixture at reflux and slowly add (dropwise) another 21 mL of 1 MDIBALltoIuene solution over a period of 40 min. Cool the reaction mixture to about 0°Cand add 700 mL of 1 M HCI (aqueous). Separate and discard the organic phase. Washthe aqueous phase with CH2C12, discard the extract, then basify the aqueous phase byadding 50% NaOH (aqueous). Extract with CHZC12, dry the extract over MgS04 andconcentrate in vacuo to give 7.30 g of the title compound, which is a racemic mixture ofenantiomers.Step B — Separation of Enantiomers:BrBr7122 The racemic title compound of Step A is separated by preparative chiralchromatography (Chiralpack® AD”, 5 cm X 50 cm column, using 20% iPrOH/hexane +0.2% diethylamine), to give the (+)-isomer and the (-)-isomer of the title compound.Physical chemical data for (+)-isomer: m.p. = 148.8°C; Mass Spec. MH+ = 469;[on] 3b5—= +65.6° (12.93 mg/2mL MeOH).Physical chemical data for (-)-isomer: m.p. = 112°C; Mass Spec. MH+ = 469;[oz 3B5.= —65.2° (3.65 mg/ mL MeOH).CA 02264513 1999-03-02wo 9s/11099 PCT/US97/15905- 47 -Step Q:Br \ Cl Br \ C1\ / \ ’N N c(cH3)3Br "-—" B’ oN Ix/K0H(+)-isomer N )\/C‘0React 1.33 g of the (+)-isomer of the title compound of PreparativeExample 8, Step B, with 1.37 g of 1-N—t-butoxy-carbonylpiperidinyl-4-5 acetic acid using substantially the same procedures as described forPreparative Example 5, Step C, to give 2.78 g of the product. Mass Spec.:MH+ = 694.0 (FAB); [0435 = +34.1° (5.45 mg/2 mL, MeOH).Step D:Br \ Cl Br \ Cl\ / \ /N C(CH3)3 NBr ('3 Br/Kfi\/O O j\/QNHO ON10 Treat 2.78 g of the product of Step C via substantially the sameprocedure as described for Preparative Example 5, Step D, to give 1.72 gof the product. m.p. = 104.1°C; Mass Spec.: MH+ = 594; [oc]g5 = +53.4°(11.42 mg/2 mL, MeOH).15 PREPARATIVE EXAMPLE 9Br \ Cl\ /N(:3 B’ NH3&3[racemic as well as (+)- and (-)-isomers]CA 02264513 1999-03-02W0 98/ 11099 PCT/U S97/ 15905-45- Br \\ /N0 Br \ Cl\ /N0 N02Combine 40.0 g (0.124 mole) of the starting ketone and 200 mL ofH2304 and cool to 0°C. Slowly add 13.78 g (0.136 mole) of KNO3 over a5 period of 1.5 hrs., then warm to room temperature and stir overnight. Workup the reaction using substantially the same procedure as described forPreparative Example 4, Step A. Chromatograph (silica gel, 20%, 30%,40%, 50% EtOAc/hexane, then 100% EtOAc) to give 28 g of the 9-nitroproduct, along with a smaller quantity of the 7-nitro product and 19 g of a10 mixture of the 7-nitro and 9-nitro compounds.Step B:Br \ Cl Br \ C1\ / ———» \ NxN0 N02 0 NH2Fteact 28 g (76.2 mmol) of the 9-nitro product of Step A, 400 mL of85% EtOH/water, 3.8 g (34.3 mmol) of CaC|2 and 38.28 g (0.685 mole) of15 Fe using substantially the same procedure as described for PreparativeExample 4, Step C, to give 24 g of the productStep C:Br \ c1 Br \ C1\ / ———» \ xN NNH0 NH2 0 Br 2Combine 13 g (38.5 mmol) of the product of Step B, 140 mL of20 HOAc and slowly add a solution of 2.95 mL (57.8 mmol) of Bra in 10 mL ofHOAc over a period of 20 min. Stir the reaction mixture at roomtemperature, then concentrate in vacuo to a residue. Add CH2Cl2 andwater, then adjust to pH = 8-9 with 50% NaOH (aqueous). Wash theW0 98/1 1099101520CA 02264513 1999-03-02PCT/U S97! 15905-49-organic phase with water, then brine and dry over Na2SO4. Concentratein vacuo to give 11.3 g of the product.Step D:Br \ c1 Br \ C1\ / ————> \ NxNO NH2 0Br BrCool 100 mL of concentrated HCI (aqueous) to 0°C, then add 5.61g (81.4 mmol) of NaNO2 and stir for 10 min. Slowly add (in portions) 11.3g (27.1 mmol) of the product of Step C and stir the mixture at 0°-3°C for2.25 hrs. Slowly add (dropwise) 180 mL of 50% H3PO2 (aqueous) andallow the mixture to stand at 0°C overnight. Slowly add (dropwise) 150mL of 50% NaOH over 30 min., to adjust to pH = 9, then extract withCH2Cl2. Wash the extract with water, then brine and dry over NagSO4.Concentrate in vacuo to a residue and chromatograph (silica gel, 2%EtOAc/ CH2Clg) to give 8.6 g of the product.Step E:Br \ Cl Br\ , ————-—»N0 BrCombine 8.6 g (21.4 mmol) of the product of Step D and 300 mL ofMeOH and cool to 0°-2°C. Add 1.21 g (32.1 mmol) of NaBH4 and stir themixture at ~O°C for1 hr. Add another 0.121 g (3.21 mmol) of NaBH4, stirfor 2 hr. at 0°C, then let stand overnight at 0°C. Concentrate in vacuo to aresidue then partition the residue between CH2Cl2 and water. Separatethe organic phase and concentrate in vacuo (50°C) to give 8.2 g of theproduct.fitfiliBrBr \ Cl\ / —————+NOH Br OH Br W0 98/1 1099101520CA 02264513 1999-03-02PCT/US97/15905-50-Combine 8.2 g (20.3 mmol) of the product of Step E and 160 mL ofCHgCl2, cool to 0°C, then slowly add (dropwise) 14.8 mL (203 mmol) ofSOC|2 over a 30 min. period. Warm the mixture to room temperature andstir for 4.5 hrs., then concentrate in vacuo to a residue, add CH2C|2 andwash with 1 N NaOH (aqueous) then brine and dry over NagSO4.Concentrate in vacuo to a residue, then add dry THF and 8.7 g (101 mmol)of piperazine and stir at room temperature overnight. Concentrate invacuo to a residue, add CH2C|2, and wash with 0.25 N NaOH (aqueous),water, then brine. Dry over NagSO4 and concentrate in vacuo to give 9.46g of the crude product. Chromatograph (silica gel, 5% MeOH/CH2Clg +NH3) to give 3.59 g of the title compound, as a racemate. ‘H NMR(CDCI3, 200 MHz): 8.43 (d, 1H); 7.55 (d, 1H); 7.45 (d, 1H); 7.11 (d, 1H);5.31 (s, 1H); 4.86-4.65 (m, 1H); 3.57-3.40 (m, 1H); 2.98-2.55 (m, 6H);2.45-2.20 (m, SH).Step G - Separation of Enantiomers: N S-(-)HThe racemic title compound from Step F (5.7 g) is chromatographedas described for Preparative Example 6, Step D, using 30% iPrOH/hexane+ 0.2% diethylamine, to give 2.88 g of the Fl-(+)-isomer and 2.77 g of theS-(-)-isomer of the title compound.Physical chemical data for the R-(+)-isomer: Mass Spec. MH+ =470.0; [a]Ԥ,5 = +12.1° (10.9 mg/2mL MeOH).Physical chemical data for the S-(-)-isomer: Mass Spec. MH+ =470.0; [0135 = -13.2° (11.51 mg/ 2mL MeOH).W0 98/ 1 1099101520CA 02264513 1999-03-02PCTIUS97/15905- -§tep H:Following essentially the same procedure as Preparative Example5, Steps C and D, the racemic title compound of Preparative Example 9 isobtained from the racemic compound of Step F. Similarly, using the (-)- or(+)- isomer from Step G, the (-)- or (+)-isomer of the title compound ofPreparative Example 9 is obtained, respectively.PFlEPAFlATlVE EXAMPLE 10BrBr \ C1 HO[racemic as well as (+)- and (-)-isomers]Step A:Br Br\ Cl\ /NNH Combine 13 g (33.3 mmol) of the title compound from PreparativeExample 4, Step E, and 300 mL of toluene at 20°C, then add 32.5 mL(32.5 mmol) of a 1 M solution of DIBAL in toluene. Heat the mixture atreflux for 1 hr., cool to 20°C, add another 32.5 mL of 1 M DIBAL solutionand heat at reflux for 1 hr. Cool the mixture to 20°C and pour it into amixture of 400 g of ice, 500 mL of EtOAc and 300 mL of 10% NaOH(aqueous). Extract the aqueous layer with CH2Cl2 (3 x 200 mL), dry theorganic layers over MgSO4, then concentrate in vacuo to a residue.Chromatograph (silica gel, 12% MeOH/CH2Cl2 + 4% NH4OH) to give 10.4g of the title compound as a racemate. Mass Spec.: MH+ = 469 (FAB).partial ‘H NMR (CDCI3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (d,1H); 7.06 (d, 1H); 3.95 (d, 1H).CA 02264513 2002-06-19-52-Stepi Separation ognantiomers:BrNHThe racemic title compound of Step A is separated by preparative chiral chromatography (Chiralpack® AD“, 5 cm X 50 cm column, using 5% iPrOH/hexane +0.2% diethylamine), to give the (+)-isomer and the (-)—isomer of the title compound.Physical chemical data for (+)-isomer: Mass Spec.MH+ = 469 (FAB); [oz 303 = +43.5° (c=0.402, EtOH); partial ‘H NMR (CDCI3, 400MHZ): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (d, 1H); 7.05 (d, 1 H); 3.95 (d, 1H).Physical chemical data for (-)—isomer: Mass Spec.MH+ = 469 (FAB); [oc]2—l:= -41.8° (C=O.328 EtOH); partial 1H NMR (CDCI3, 400MHz): 8.38 (s, 1H); 7.57 (s, 1H); 7.27 (cl, 1H); 7.05 (d, 1H); 3.95 (d, 1H).§t_<2LC_IFollowing the procedure of Preparative Example 9. Step H, the racemiccompound, the (+)-isomer or the (-)—isomer of the title compound of PreparativeExample 10 can be obtained. .....m......u...«.......m «mm.CA 02264513 1999-03-02WO 98/11099 PCT/US97/15905- 53 _PREPARATIVE EXAMPLE 11Br \ Cl\ /NE”) NHO[racemic as well as Fl-(+)- and S-(-)-isomers]The compoundBr / C1\\NEN)ll5 H10152025is prepared according to the procedures of Preparative Example 40 of WO95/10516 (published April 20, 1995), by following the proceduresdescribed in Example 193 of WO 95/10516.The (+)- and (-)-isomers can be separated by following essentiallythe same procedure as Step D of Preparative Example 6.Physical chemical data for the Fl-(+)-isomer: 13C NMR (CDCI3):155.8 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3 (C);133.4 (C); 132.0 (CH); 129.9 (CH); 125.6 (CH); 119.3 (C); 79.1 (CH);52.3 (CH2); 52.3 (OH); 45.6 (CH2); 45.6 (CH2): 30.0 (CH2); 29.8 (CH2).[oqfis = +25.8° (8.46 mg/2 mL MeOH).Physical chemical data for the S-(-)-isomer: 13C NMR (CDCI3):155.9 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3 (C);133.3 (C); 132.0 (CH); 129.9 (CH); 125.5 (CH); 119.2 (C); 79.1 (CH);52.5 (CH2); 52.5 (CH); 45.7 (CH2): 45.7 (CH2); 30.0 (CH2): 29.3 (CH2).M35 = -27.9° (8.90 mg/2 mL MeOH).Following essentially the same procedure as Preparative Example5, Steps C and D, the racemic compound, (+)-isomer or (-)-isomer of thetitle compound of Preparative Example 11 can be obtained from thecorresponding racemic compound, (+)-isomer or (-)-isomer of thecompoundW0 98/1 1099CA 02264513 1999-03-02PCT/U S97/ 15905-54-Br /\ c1(Preparative Example 8) (0.11 g, 0.19 mmol), anhydrousdimethylformamide (2 mL), 2-bromoacetamide (0.027 g, 0.2 mmol) andanhydrous sodium carbonate (0.04 g, 0.38 mmol) were stirred at room10 temperature overnight. The mixture was diluted with water, filtered andthe solids washed with water. The solids were diluted withdichloromethane, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to afford the compound of Formula 2.0 as a solid(0.084 g, 68%, mp 131°C).15CA 02264513 1999-03-02 W0 98/1 1099 PCT/US97/15905- 55 -EXAMPLE 2Step A:0c1\)k01 + n ——~ 0c1 K/O O5 To a stirred solution of morpholine (1.62 mL, 18.5 mmol) and101520triethylamine (2.62 mL, 18.8 mmol) in anhydrous diethyl ether (100 mL)was added chloroacetyl chloride (1.5 mL, 1.02 eq) dissolved in diethylether (10 mL) at 0°C. After stirring for 0.5 hours, water and 1 Mhydrochloric acid were added and the mixture was shaken. The organicphase was separated and washed with brine and 1 N aqueous sodiumhydroxide, then dried over anhydrous magnesium sulfate. Filtration andconcentration in vacuo afforded the title compound (0.05 g) as a light oil.Step B: O(16.0) + °‘JkNfi :*V’ A mixture of the compound of Formula 16.0 (Preparative Example8) (0.10 g, 0.17 mmol), anhydrous dimethylformamide (4 mL), the titlecompound from Step A of Example 2 (0.051 g, 0.31 mmol) and anhydroussodium carbonate (0.036 g, 0.34 mmol) were stirred at room temperatureovernight. The mixture was diluted with water, filtered and the solidswashed with water. The solids were diluted with dichloromethane, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo toafford a solid (0.077 g). Purification by preparative plate chromatographyW0 98/ 110991015CA 02264513 1999-03-02PCT/US97/15905- 55 -(silica gel) using 5% methanol—dichloromethane and concentratedammonium hydroxide using 5% methanol-dichloromethane andconcentrated ammonium hydroxide provided the compound of Formula7.0 (0.063 g, 52%, mp 126.9-131.9°C).EXAMPLE;/[L )rC“30 CH3 Step A:c1\)J\N/\|HO \N/\|C1\)]\ +K/N 0 CH3 ______ |\/N 0 CH3C1 CH Y KC}!3 CH3 30 CH3 0To a stirred solution of t-butyl-1-piperazine carboxylate (2.12 g, 11.4mmol) and triethylamine (1.62 mL, 11.6 mmol) in anhydrous diethyl ether(100 mL) was added chloroacetyl chloride (0.92 mL, 1.02 eq) dissolved indiethyl ether (10 mL) at 0°C. After stirring for 0.5 hours, water and 1 Mhydrochloric acid were added and the mixture was shaken. The organicphase was separated and washed with brine and 1 N aqueous sodiumhydroxide, then dried over anhydrous magnesium sulfate. Filtration andconcentration in vacuo afforded the title compound (2.37 g) as a light oil.CA 02264513 1999-03-02W0 98/11099 PCT /US97/15905-57-Step B: A mixture of the compound of Formula 16.0 (Preparative Example8) (0.25 g, 0.41 mmol), anhydrous dimethylformamide (5 mL), the title5 compound from Step A of Example 3 (0.12 g, 0.46 mmol) and anhydroussodium carbonate (0.053 g, 0.50 mmol) were stirred at room temperatureovernight. The mixture .was diluted with water, filtered and the solidswashed with water. The solids were diluted with dichloromethane, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo to10 afford a solid (0.296 g). Purification by preparative plate chromatography(silica gel) using 5% methanol-dichloromethane and concentratedammonium hydroxide using 5% methanol-dichloromethane andconcentrated ammonium hydroxide provided the compound of Formula8.0 (0.17 g, 49°/o, mp 139.1-141.2°C).15EXAMPLE 4 To the compound of Formula 8.0 (Example 3) (0.12 g) dissolved inanhydrous dichloromethane (25 mL) was added trifluoroacetic acid (1 mL)20 and the resulting solution was stirred at room temperature for 2 hour. 50°/oW0 98/110991015‘20CA 02264513 1999-03-02PCT/US97/ 15905- 58 -Aqueous sodium hydroxide was added slowly followed bydichloromethane and brine. The mixture was shaken well, the organicphase was washed with water, separated and dried over anhydrousmagnesium sulfate. Filtration and concentration in vacuo provided aresidue which was purified by preparative plate chromatography (silicagel) using 5% methanol-dichloromethane and concentrated ammoniumhydroxide using 5% methanol-dichloromethane and concentratedammonium hydroxide affording the compound of Formula 9.0 (0.07 g,71%, mp 130.3-135.2°C).EXAMPLE 5 A mixture of the compound of Formula 16.0 (Preparative Example8) (0.51 g, 0.85 mmol), anhydrous dimethylformamide (10 mL), tert-butylbromoacetate (0.13 mL, 0.89 mmol) and anhydrous sodiumcarbonate (0.18 g, 1.7 mmol) were stirred at room temperature overnight.The mixture was diluted with water, filtered and the solids washed withwater. The solids were diluted with dichloromethane, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to affordthe compound of Formula 11.0 as a solid (0.47 g, 79%, mp 107-112°C).EXAMPLE 6 (16.0)——--——>CA 02264513 1999-03-02W0 98/1 1099 PCT/US97/15905-59-Following procedures similar to those of Example 1, the compoundof Formula 16.0 was reacted with 2-chloro-N-methoxy-N-methylacetamideto produce a compound of Formula 3Ø (Yield 40%, mp 116-120°C).5 EXAMPLE 7 (16.0) —-——-—> (4-0) ,cH2cH3N\N W cH2cH3o0Following procedures similar to those of Example 1, the compoundof Formula 16.0 was reacted with 2-chloro-N,N—diethylacetamide toproduce a compound of Formula 4.0 (Yield 62%, mp 110-114°C).10EXAMPLE 8 (15.0) —-———> (5-0)Following procedures similar to those of Example 1, the compoundof Formula 16.0 was reacted with N-chloroacetyl-benzylamine (i.e.,N\c1/Y H15 0N-chloroacetyl-N-benzylamine) to produce a compound of Formula 5.0(Yield 39%, mp 112-116°C).CA 02264513 1999-03-02W0 98/1 1099 PCT/US97/ 15905-50-EXAMPLE 2 Following procedures similar to those of Example 1, the compoundof Formula 16.0 was reacted with 1-bromoacetamido-1-deoxy-B-D-5 galactopyranose to produce a compound of Formula 6.0 (Yield 23%, mp187.0-189.9°C).EXAMPLE 10 10 Following procedures similar to those of Example 2, the compoundof Formula 16.0 was reacted with 1-(2-chloroacetyl)-indoline to produce acompound of Formula 10ØEXAMPLE 11 (11.0)--———————> (11-1)15A mixture of the compound of Formula 11.0 (Example 5) (0.40 g),dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred atroom temperature for 10 days. The mixture was neutralized to pH 7 withCA 02264513 2002-12-04_(,1,_1N NaOH (aq), diluted with methanol and concentrated in vacuo. thesolids were washed with absolute ethanol, filtered and the filtrate wasconcentrated in vacuo. Dichloromethane saturated with hydrogen .chloride (gas) was added to the resulting cream colored foam and afterstirring for 30 minutes at room temperature, the mixture was filtered andthe solid dried under vacuum to provide the compound of Formula 11.1(1.0 g, MH+ = 652) along with sodium chloride as an impurity.EXAMELEJZBr /\ c1N H (20.0)J'\/(:71 /WA onO onDissolve 1.0 equivalent of the (+) product of Preparative Example 8, StepD, in dichloromethane containing 1.1 equivalents of glycidol and stirfor 48 hr.Concentrate under vacuum and chromatograph the residue on silica gel to obtainthe produce as a white solid.ASSAYSFPT |C5o (inhibition of famesyl protein transferase, in vitro enzyme assay)and CO8 Cell lC50 (Cell Based Assay) were determined following the assayprocedures described in WO 95/10516, published April 20, 1995. GGPT lC50(inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), Cell MatAssay, and anti tumor activity (in vivo anti tumor studies) could be determined bythe assay procedures described in W095/10516.Additional assays can be carried out by following essentially the sameprocedure as described above, but with substitution of alternative indicator tumorcell lines in place of the T24—BAG cells. The assays can be conducted using eitherDLD—1-BAG human colon carcinoma cells expressing an activated K ras gene orSW620-BAG human colon carcinoma cells expressing an activated K—ras gene.Using other tumorW0 98/1 1099101520253035CA 02264513 1999-03-02PCT/US97/15905-32-cell lines known in the art, the activity of the compounds of this inventionagainst other types of cancer cells could be demonstrated.Soft Agar Assay:Anchorage-independent growth is a characteristic of tumorigeniccell lines. Human tumor cells are suspended in growth mediumcontaining 0.3% agarose and an indicated concentration of a famesyltransferase inhibitor. The solution is overlayed onto growth mediumsolidified with 0.6% agarose containing the same concentration of farnesyltransferase inhibitor as the top layer. After the top layer is solidified, platesare incubated for 10-16 days at 37°C under 5% CO2 to allow colonyoutgrowth. After incubation, the colonies are stained by overlaying theagar with a solution of MTl' (3-[4,5-dimethyl-thiazo|-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in PBS). Coloniescan be counted and the lC5o's can be determined.Compounds 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 and 20.0 'had an FPT |C5o (H-ras) within the range of 1.8 to 28nM (nanomolar).Compounds 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0 and 9.0 had an FPT lC5o(K-ras) within the range. of 8.6 to 51 .9nMCompounds 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 and 20.0 had aCos Cell lC5o within the range of 6 to 840 nM.Compounds 2.0, 3.0, 4.0, 6.0, 7.0, 8.0, 9.0, and 20.0 had a SoftAgar FPT lC5o within the range of 60 to >500nMFor preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70percent active ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage formssuitable for oral administration.For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds,allowed to cool and thereby solidify.W0 98/ 1 1099101520253035CA 02264513 1999-03-02PCT/U S97/ 15905- 53 -Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection.Liquid form preparations may also include solutions for intranasaladministration.Aerosol preparations suitable for inhalation may include solutionsand solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for either oral orparenteral administration. Such liquid forms include solutions,suspensions and emulsions.The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art for thispurpose.Preferably the compound is administered orally.Preferably, the pharmaceutical preparation is in unit dosage form.In such form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effective amount toachieve the desired purpose.The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg. to 300 mg, according to the particular application.The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is within theskill of the art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage maybe divided and administered in portions during the day if desired.The amount and frequency of administration of the compounds ofthe invention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinician consideringsuch factors as age, condition and size of the patient as well as severity ofthe symptoms being treated. A typical recommended dosage regimen isW0 98/ 110991015CA 02264513 1999-03-02PCT/US97/15905- 54 -oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000mg/day, in two to four divided doses to block tumor growth. Thecompounds are non-toxic when administered within this dosage range.The following are examples of pharmaceutical dosage forms whichcontain a compound of the invention. The scope of the invention in itspharmaceutical composition aspect is not to be limited by the examplesprovided.Pharmaceutical Dosage Form ExamplesEXAMPl_.E A - Tab_I_et§No. lnL_edients mg/tablet mg/ tablet1. Active compound 100 5002. Lactose USP 122 1 133. Corn Starch, Food Grade, 30 40as a 10% paste inPurified Water4. Corn Starch, Food Grade 45 405. Magnesium Stearate _____§ :7Total 300 700Method of ManufactureMix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.Granulate the mixture with Item No. 3. Mill the damp granules through acoarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules.Screen the dried granules if necessary and mix with item No. 4 and mixfor 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compressthe mixture to appropriate size and weigh on a suitable tablet machine.EXAMPLE B - CagsulesNo. Ingredient mg/capsule mg/capsule1. Active compound 100 5002. Lactose USP 106 1233. Corn Starch, Food Grade 40 704. Magnesium Stearate NF £ ___7_Total 253 700W0 98/1 109910CA 02264513 1999-03-02PCT/U S97/ 15905-55-Method of ManufactureMix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes.Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.While the present invention has been described in conjunction withthe specific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill in the art.All such alternatives, modifications and variations are intended to fallwithin the spirit and scope of the present invention.

Claims (37)

CLAIMS:

1. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR9 wherein R9 is O-, -CH3 or -(CH2)n CO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2; or each of a, b, c, and d are independently selected from CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, -CF3, -OR10, -COR10, -SR10, -S(O)t R11 (wherein t is 0, 1 or 2), -SCN, -N(R10)2, -NR10R11, -NO2, -OC(O)R10, -CO2R10, -OCO2R11, -CN, -NHC(O)R10, -NHSO2R10, -CONHR10, -CONHCH2CH2OH, -NR10COOR11, -SR11C(O)OR11, -SR11N(R75)2 wherein each R75 is independently selected from H and -C(O)OR11, benzotriazol-1-yloxy, tetrazol-5-ylthio, or alkyl substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR10 or -CO2R10; wherein R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, R7 and R8 each independently represents H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with -OR10, -SR10, -S(O)t R11, -NR10COOR11, -N(R10)2, -NO2, -COR10, -OCOR10, -OCO2R11, -CO2R10, OPO3R10 or R5 is combined with R6 to represent =O
or =S and/or R7 is combined with R8 to represent =O or =S; wherein R10 represents H, alkyl, aryl, or aralkyl;
R11 represents alkyl or aryl;
X represents N, CH or C, which C may contain an optional double bond to carbon atom 11;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B
independently represent -R10, halo, -OR11, -OCO2R11 or -OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B
each independently represent H2, -(OR11)2, H and halo, dihalo, alkyl and H, (alkyl)2, -H and -OC(O)R10, H and -OR10, =O, aryl and H, =NOR10 or -O-(CH2)p-O- wherein p is 2, 3 or 4; and W represents a group selected from:

wherein:
R12 is selected from the group consisting of: (1) H; (2) alkyl; (3) aryl;
(4) aralkyl;
R13 is selected from the group consisting of: (1) H; (2) alkyl; (3) alkoxy;
(4) heterocycloalkyl; (5) aryl; and (6) aralkyl; wherein said heterocycloalkyl is a saturated, branched or unbranched carbocyclic ring containing from 3 to 15 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from -O-, -S- or -NR10-;
tetrahydropyranyl substituted with a hydroxy or hydroxyalkyl;
wherein hydroxyalkyl is defined as hydroxymethyl;
R14 is selected from the group consisting of: (1) H; (2) alkyl; (3) aryl;
and (4) heteroaryl; said heteroaryl represents cyclic groups, optionally substituted with R3 and R4, having at least one heteroatom selected from O, S, or N, said heteroatom interrupting a carbocyclic ring structure and having sufficient number of delocalized pi electrons to provide aromatic character, with the heteroaryl containing from 2 to 14 carbon atoms;
ring represents a heterocycloalkyl ring wherein Y comprises 4-5 carbon atoms and optionally a hetero atom selected from the group consisting of: NH, NR15, O and S, and the remaining carbon atoms optionally having an aryl ring fused thereto, and cyclic groups optionally substituted with R3 and R4;
R15 represents -C(O)OR16; and R16 represents alkyl;

said alkyl is hereinbefore defined as a straight and branched carbon chain containing from one to twenty carbon atoms;
said alkynyl is hereinbefore defined as a straight and branched carbon chain having at least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms;
said alkenyl is hereinbefore defined as a straight and branched carbon chain having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms;
said aryl is hereinbefore defined as a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one to three, halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, -COOR10 or -NO2;
said aralkyl is hereinbefore defined asa combined group of said aryl bound to said alkyl;
said halo is selected from the group consisting of fluoro, chloro, bromo and iodo;
said alkoxy is hereinbefore defined as an -O- bound to said alkyl.

2. The compound according to Claim 1, wherein said alkynyl has from 2 to 6 carbon atoms.

3. The compound according to Claim 1 or 2, wherein said alkenyl has from 2 to 6 carbon atoms.

4. The compound according to any one of Claims 1 to 3, wherein said alkenyl has from 3 to 6 carbon atoms.

5. The compound according to any one of Claims 1 to 4, wherein said alkyl has from 1 to 6 carbon atoms.

6. The compound according to any one of Claims 1 to 5, wherein said heterocycloalkyl as defined in R13 has from 4 to 6 carbon atoms.

7. The compound according to any one of Claims 1 to 6, wherein said heterocycloalkyl is selected from a group consisting of:
(a) 2- or 3-tetrahydrofuranyl;
(b) 2- or 3- tetrahydrothienyl;
(c) 2-, 3- or 4-piperidinyl;
(d) 2- or 3-pyrrolidinyl;
(e) 2- or 3-piperazinyl;
(f) 2- or 4-dioxanyl;
(g) tetrahydropyranyl; and (h) tetrahydropyranyl substituted with a hydroxy or hydroxyalkyl;
wherein hydroxylalkyl is defined as hydroxymethyl.

8. The compound according to any one of Claims 1 to 7, wherein said heteroaryl ring comprises 4-5 carbon atoms.

9. The compound according to any one of Claims 1 to 8, wherein said heteroaryl ring is selected from a group consisting of:

(a) (2-, 4- or 5-)imidazolyl;
(b) triazolyl;
(c) (2-, 3- or 4-)pyridyl; and (d) pyridyl N-oxide.

10. The compound according to Claim 9, wherein said pyridyl N-oxide is substituted with R3 and R4.

11. The compound according to Claim 10, wherein said pyridyl N-oxide is

12. The compound according to any one of Claims 1 to 10 wherein R2 is H; R1 is selected from the group consisting of: Br and Cl; R3 is selected from the group consisting of: Br and Cl; R4 is selected from the group consisting of: H, Br and Cl; R5, R6, R7 and R8 are H; A and B are each H2;
and the optional bond between C5 and C6 is absent.

13. The compound according to any one of Claims 1 to 11 wherein W is selected from the group consisting of:

wherein:
(1) R12 is selected from the group consisting of: H, alkyl and aralkyl; and (2) R13 is selected from the group consisting of: H, alkyl, alkoxy, aralkyl, and heterocycloalkyl;

wherein is selected from the group consisting of:

wherein R14 is H or alkyl.

14. The compound according to any one of Claims 1 to 13, wherein R4 is H.

15. The compound according to any one of Claims 1 to 13, wherein R4 is selected from the group consisting of: Cl or Br.

16. The compound according to any one of Claims 1 to 15, wherein X is CH.

17. The compound according to any one of Claims 1 to 16 wherein R12 is selected from: H, methyl or ethyl; and R13 is selected from: H, methyl, ethyl, methoxy, benzyl, or R14 represents H or -C(CH3).

18. The compound according to Claim 1 selected from:

wherein R1, R3 and R4 are each independently a halo; and A, B, X and W are as defined in Claim 1.

19. The compound according to Claim 18, wherein R2 is H; R1 , R3 and R4 are each independently selected from the group consisting of: Br and Cl; R5, R6, R7 and R8 are H; A and B are each H2; and the optional bond between C5 and C6 is absent.

20. The compound according to Claim 18 or 19, wherein W is selected from the group consisting of:

(A) wherein:
(1) R12 is selected from the group consisting of: H, alkyl and aralkyl; and (2) R13 is selected from the group consisting of: H, alkyl, alkoxy, aralkyl, and heterocycloalkyl;
(B) wherein is selected from the group consisting of:

and ;and wherein R14 is H or alkyl.

21. A compound according to any one of Claims 18 to 20, wherein X
is CH.

22. A compound according to any one of Claims 18 to 21, wherein R12 is selected from H, methyl and ethyl and R13 is selected from: H, methyl, ethyl, methoxy, benzyl, or ; and R14 represents H or -C(CH3).

23. The compound according to any one of Claims 18 to 22 wherein, R1 is Br, and R3 is Cl; and R4 is Br.

23. The compound according to any one of Claims 18 to 22 wherein, R1 is Br, and R3 is Cl; and R4 is Br.

24. The compound of any of Claims 1-23 wherein said compound is a compound of the formula:

25. The compound according to Claim 1 selected from:

26. Use of a compound as defined in any one of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament to treat tumor cells.

27. Use according Claim 26, wherein the tumor cells are selected from the group consisting of pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells and prostate tumor cells.

28. Use of a compound as defined in any one of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament to inhibit farnesyl protein transferase.

29. A tumor cell treating pharmaceutical composition comprising an effective tumor cell treating amount of a compound as defined in any one of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.

30. A pharmaceutical composition according to Claim 29, wherein the tumor cells treated are selected from the group consisting of pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells and prostate tumor cells.

31. A farnesyl protein transferase inhibiting pharmaceutical composition comprising an effective farnesyl protein transferase inhibiting amount of a compound as defined in any one of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.

32. A compound as defined in any one of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, for use in treating tumor cells.

33. A compound according to Claim 32, wherein the tumor cells treated are selected from the group consisting of pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells and prostate tumor cells.

34. A compound as defined in any one of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting farnesyl protein transferase.

35. A pharmaceutical composition for inhibiting abnormal growth of cells comprising an effective amount of a compound of any of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.

36. The use of a compound of any of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof for the treatment of tumor cells.

37. The use of a compound of any of Claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof for the inhibition of farnesyl protein transferase.